Interplay between innate and adaptive immune response is currently emerging as a novel topic in immunology with a potential impact in medical sciences. Among many different molecules participating in these processes is the family of antigen-presenting class IMHC, which orchestrate NK cell and T cell responses and regulate their interactions. The focus of this proposal is the nonclassical (class Ib) MHC, Qa-2, similar to class la and to human class Ib, HLA-G. Multiple genes and multiple alternatively spliced transcripts with potentially different capabilities or regulating immunity encode Qa-2. Our laboratory played a major role in defining the peptide-binding properties, the crystal structure and the role in NK cell inhibition by GPl-linked, canonical Qa-2. We now plan to use our past expertise and reagents to (1) identify novel isoforms of Qa-2 and determine their expression patterns;(2) evaluate their interactions with components of the innate immune system (NK cells); and (3) study their function in inducing protective adaptive immune response during tumor rejection. The specific hypotheses to be addressed include the notion that peptide-loaded Qa-2 engage NK and T cell receptors and the speculation that they play a specialized role in elimination of stressed/malignantly-transformed cells.